In patients with transverse lesions of the spinal cord above the sixth thoracic vertebra, noxious cutaneous stimuli or, more commonly, urinary bladder or rectal distention can trigger an autonomic hyperreflexia (dysreflexia) that is characterized by an exaggerated activation of the sympathetic nervous system below the lesion. The extreme vasoconstriction and ensuing hypertension can be life-threatening. Considerable evidence indicates that afferent activation of a spinal sympathetic reflex is the neural substrate underlying the dysreflexia, although receptor supersensitivity amplifies the efferent responses. The spinal sympathetic reflex arc is under a strong descending inhibition when the spinal cord is intact. The long-term goal of this research is to ameliorate the autonomic hyperreflexia in spinal patients by identifying pharmacologic agents that mimic the tonic descending inhibition of the spinal sympathetic reflex. In this proposal, electrophysiologic techniques will be applied following cervical spinal cord transection in unanesthetized, decerebrate rats to identify the neuronal elements comprising the spinal somatosympathetic reflex pathway. These results will provide the basis for further experiments in rats with intact spinal cords to characterize the site of action of the descending inhibition by determining which element(s) of the spinal sympathetic reflex pathway are unresponsive to afferent stimulation. Transection and excitotoxic lesions of local cell bodies will be used to identify the origin of the descending pathway maintaining inhibition of the spinal sympathetic reflex. Guided by the nature of the neurotransmitters localized in cells within this region and by previous data on the effects of catecholaminergic and GABAergic agents, agonist drugs will be selected and tested for their ability to inhibit the reflex in animals with transected spinal cords. Conversely, the appropriate antagonist compounds should be able to disinhibit the spinal sympathetic reflex in the intact animal. These data will provide new information on an important component of the descending regulation of spinal sympathetic circuits and indicate promising therapeutic approaches to the management of autonomic dysreflexia following high spinal cord injury.